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Vril Dox was a Coluan scientist. At some point, he cloned himself to get a lab assistant; the clone would later be called Vril Dox II. He acquired a spaceship and went on a journey through space, acquiring knowledge and using his robotic drones to capture living organisms of various alien species. Along the way, he came to Krypton some time during the lifetime of General Zod, and kidnapped the entire city of Kandor, miniaturizing it in his spaceship. He also created a remote scout unit, which was programmed to think it was the original Vril Dox.

The remote scout unit came to Earth as a cloud of nano technological robots, and took over the body of sideshow mentalist Milton Fine, who worked under the alias "Brainiac". Needing cranial fluid to maintain his possession of Fine, Dox went on a murder spree. He discovered Fine had genuine psychic powers, which he frequently used on Superman. Brainiac was later captured by Lex Luthor, but used his powers to wrest control of Lexcorp away from him. Under his mental domination, Lexcorp scientists recreated his Coluan form. The diodes in his head now increased and stabilised his mental powers, as well as allowing him direct access to computer banks. He continued to plague Superman, using a combination of mental powers and computer control. On one occasion he began to shrink cities. Following the loss of Milton Fine's body, Vril Dox would place his consciousness in a robot body he called Brainiac 2.5. He became briefly obsessed with gaining Superman's form. Brainiac revealed he had placed a sleeper virus in Lexcorp's Y2K bug safeguards. This was intended to dramatically boost his abilities. Instead it allowed Brainiac 13 to arrive from the 64th century. Brainiac 13 stole Brainiac's body and placed Brainiac mind in the body of Lena Luthor. Brainiac 13 then converted Metropolis into a futuristic replica of itself, Lex Luthor traded his daughter, Lena Luthor, to Brainiac 13 in exchange for being given control of his B13 Technology. Brainiac 2.5 left with Brainiac 13. During the Imperiex attack, Brainiac 13 and Brainiac 2.5 became involved. Although initially working against Imperiex with the heroes of Earth, they tried to double-cross them later on. However, this plan backfired; Brainiac 13 was sent back through time to die in the Big Bang and Brainiac 2.5 lost control of Lena Luthor. This copy of Brainiac is now considered dead.

Later, a future version of Brainiac called Brainiac 6 used Indigo to kill Donna Troy. This version of Brainiac was trying to clone its body using a secret Lexcorps facility. After the Infinte Crisis, a copy of Brainiac composed of nanoscale robots invaded a Waynetech robotics facility and tried to gain a new body a prototype OMAC unit built with B13 Technology. Controlling Metallo and the Metal Men, he fought Superman and Batman for the OMAC, but was ultimately defeated

A drone unit came to earth and fought Superman, drawing blood for research by Brainiac. After Supergirl informed Superman of Brainiac's true nature, Brainiac brought his ship above Earth, deactivating all technology on the surface, capturing Superman and preparing to steal Metropolis; as soon as he had Metropolis, he planned to destroy the Sun with a missile, taking the rest of the Earth with it. Supergirl stopped his missile, while Superman broke free in his ship and carried him to the surface of the Earth, where he knocked him out. However, as Superman was distracted with saving Metropolis & Kandor, Brainiac tried to attack the Kent farm; Jonathan Kent died as a result. Brainiac was captured by the United States government and turned over to Project 7734. Lex Luthor attempted to flee the Project with Brainiac, but Brainiac resisted, citing a plan that he had. How this plan will unfold is unknown, but it involves an alliace between the two masterminds against Superman.